Blood vessels from different sites and species may exhibit heterogeneous responses to the same stimuli. The role of the different components of the blood vessel wall in the causation of these dissimilar responses is largely unknown. The prime purpose of the proposed studies is to examine the contribution of the endothelium. Such studies, however, also demand knowledge of the characteristics of the arterial and venous smooth muscle. Most experiments will be performed on isolated blood vessels; confirmation of the results obtained will be sought in the intact organism. Preparations will be taken from normotensive dogs, pigs, rabbits, rats and man: studies will also be performed on blood vessels from dogs and rats with hypertension, or from dogs where cerebral vasospasm has been induced. Responses of vascular smooth muscle will be measured as changes in isometric tension or in resistance. Preparations with and without endothelium will be compared to assess the role of the endothelial cells; the presence or absence of endothelium will be confirmed histologically. Particular attention will be paid to the response to norepinephrine, prostaglandins, 5-hydroxytryptamine, aggregating platelets, thrombin and anoxia, since earlier work and preliminary studies implicate the endothelium as an important modulator of these responses. When the endothelium is involved, studies will be performed to see if this is uniform or peculiar to certain blood vessels, and whether or not it is species specific. Other experiments will examine the possible mechanisms underlying the endothelial modulation and the smooth muscle responses. To do so will require electrophysiological measurements and examination of the metabolism of arachidonic acid as well as determination of Ca++ exchanges. It is expected that the knowledge gained will help explain the heterogeneous behavior of blood vessels, and provide new information on the role of the active components of the blood vessel wall in hypertension and in spasm of cerebral, coronary and digital vessels.